REPORT about the experimental study of embryotoxicity and influence on the reproductive function of the substance of the preparation Of "arbidol"

 

 

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INTRODUCTION

 

The substance of the preparation Of "arbidol" is given for the studies BY THE PRIVATELY HELD COMPANY Of "masterklon" (Moscow) of series 0705014, 0705015, 0705016; ND to the substance is registered on  ERREGIERRE S.p.A.

 

The preparation Of "arbidol" is the antiviral and immunostimulating means, it renders the immunomodulating and anti-influenza action, specifically suppresses the viruses of influenza A and B prevents contact and penetration of viruses into the cell, suppressing the confluence of the lipid shell of virus with the cellular membranes. It possesses the interferonindutsiruyushchim action, it stimulates the humoral and cellular reactions of immunity, the phagocytic function of macrophages, increases the stability of organism to the virus infections. Is reduced the frequency of the development of the complications, connected with the virus infection, and also the aggravations of chronic bacterial diseases.

 

Therapeutic effectiveness with the virus infections is manifested in reduction in the manifestation of general intoxication and clinical phenomena, shortening of the duration of disease.

 

According to literature data "arbidol" it relates to the slightly toxic preparations (LD 50 < 4g/kg). Does not render any negative action on the human organism during the oral application at the recommended doses.

 

It adapts with:

influenza A also in (including of those complicated by bronchitis and pneumonia) - to preventive maintenance and treatment in adult and children;

second immunodeficient states;

the complex therapy of chronic bronchitis, pneumonia and relapsing herpetic infection;

to the preventive maintenance of postoperative infectious complications and normalization of immune status in adult;

of the complex therapy of the sharp intestinal infections of rotavirusnoy etiology in children it is older than 2 years.

 

It is established that the application of preparation Of "arbidol" in rats at doses 50 and 500 mg/kg for a period of 130 days does not lead to lethality and development of the irreversible pathologic changes (T.A. Of gus'kova. Toxicology of medicines. M., "Russian doctor", 2003, s. 103).

 

For the release of preparation as the medicine, permitted to the application in man, conducting the complex of tests on the development of his possible embryotoxicity and undesirable side-line action on the reproductive function is required.

 

The present investigations were carry ouied in accordance with the "operating instructions on the study of the reproductive toxicity of pharmacological substances" (in the book "management on the experimental (preclinical) study of new pharmacological substances", M., Minzdrav RF, "remedium", s. 39-46) in the institute of the toxicology FMBA of Russia. In addition to this, was preliminarily studied the sharp toxicity of substance in accordance with the "rules of preclinical studies of safety and effectiveness of pharmacological substances" (in the book: "management on the experimental (preclinical) study of new pharmacological substances", M., Minzdrav RF, "remedium", 2000, s. 7-17) and by the "operating instructions on the study of the systemic toxic effect of pharmacological substances" (there, s.18-24).

 

 

1. Study of the sharp toxicity

 

1.1. Materials and the methods

 

Experiments were carried out on the white nonlinear rats and the mice both floor.

 

Animals entered from the nursery Rappolovo, Saint Petersburg. Age of the rats of 2.5-3 months, the mass of 150-160 g. the age of mice 2-2.5 mo., mass 18-20 g.

 

The duration of quarantine (acclimatizing period) for all animals was 14 days. The daily inspection of each animal (behavior and the general state) was carried out during the quarantine, twice during the day of animals they observed in the cells (morbidity and mortality). Before beginning a study the animals, that correspond to the criteria of the start in experiment, were distributed to the groups with the aid of the method of randomization. The animals, that do not correspond to criteria, were excluded from a study during the quarantine.

 

Cells with animals were placed into the separate rooms. Light regime: 12 it is hour - light, 12 it is hour - the darkness. The temperature of air was maintained in the limits of 19-25°C, relative humidity - 50-70%. Temperature and humidity of air were recorded daily. With a change in the weather conditions was checked the exchange of air in the accomodation with the aid of the anemometer and by measuring the content in air of carbon dioxide and ammonia. The regime of ventilation, which ensures about 15 volumes of accomodation an hour, was established, concentration CO 2 not more than 0.15 volumetric %, ammonia - not more than 0.001 mg/l.

 

During a study each animal was inspected daily. Inspection included the estimation of general behavior and general state of animals.

 

Daily all groups of animals were inspected in the cells: immediately after the injection of preparation and at the end of the day.

 

For the calculation the consumptions of water and food of rat were placed into the exchange cells.

 

A pathomorphological study included nekropsiyu, macroscopic study, weighing and histological study of internal organs. Nekropsiya was carried out under the direct observation patomorfologa. After euthanasia animals were thoroughly inspected to the object of external pathologic it was indicative. The inspection of mucous membranes ZHKT made it possible to estimate the local- irritating action of the preparation being investigated. The study of the state of breast and abdominal cavity and the macro- and microscopic examination of internal organs was carry ouied.

 

Enumeration of the organs, which was subject to the weighing:

Heart.

Lungs without or with the trachea.

Thymus.

Liver.

Spleen.

Kidneys.

Adrenal glands.

Eggs (two) - males.

Ovaries (two) - female.

Brain.

 

The accuracy of those utilized it was weight verified prior to the beginning of a study.

 

Enumeration of the organs, which was subject to the macroscopic study:

Lymph nodes.

Mammary glands - female.

Aorta.

Heart.

Larynx.

Trachea.

Lungs with bronchi (two).

Thymus.

Gullet.

Stomach (ferrous and agranular divisions).

y2-perstnaya gut.

Small intestine.

Thick bowels.

Liver (two portions).

The pancreas.

Spleen.

Kidneys (two).

Adrenal glands.

The bladder.

Womb (both horns and neck) - female.

Eggs together with epididimusami (two) - males.

Ovaries (two) - female.

Submaxillary salivary gland with the lymph nodes.

Shchitovidnaya/parashchitovidnaya gland.

Brain (3 divisions: front, average and rear).

 

Statistical processing of the results of a study was conducted through Student- Fisher.

 

 

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1.2. Results of the study

 

For determining the indices of sharp toxicity the preparation (in the form of the freshly prepared aqueous solution) was introduced to white mice and to the rats both floor it is intragastric (v/zh) through the atraumatic metallic probe at the increasing doses according to Litchfield- Wilcockson. The calculations of mean lethal doses conducted through V.B. Prozorovskomu (pharmacology and toxicology, 1978, No. 4, s. 497-502). For achievement of the large doses of preparation introduction achieved repeatedly with the interval 20-30 minutes during I it was hour. Control animals obtained the introductions of solvent (distilled water) analogous in the volumes.

 

The period of observation was 14 days. Recorded indices: lethality, the time of loss, the symptomatology of poisoning, the daily observation of general state and behavior, weighing to the introduction, to 7 and 14 days of observation, the volumes of the consumption of fodder and water (for this animals they were placed in the exchange cells of Italian firm "Texnoplast"), a dissection and a macroscopic study of all perished and survived animals at the end of the study (euthanasia it were achieved by an overdose of ether), the determination of the mass coefficients of internal organs.

 

1.2.1. Toxicometry

 

The dependent on the dose substances of the preparation Of "arbidol" lethal effects are represented in tables 1.2.1.1-1.2.1.4.

 

Table 1.2.1.1. Toxicity of the preparation of "arbidol" with v/zh introduction to the male mice

 

Dose, mg/kg                Effect, palo/vsego

2500                            0/5

3160                            0/5

4000                            1/5

5000                            2/5

6130                            3/5

7940                            4/5

10000                          5/5

 

LD50 = of 5320 В± 500 mg/kg

 

LD16 = of 3280 В± 290 mg/kg

 

LD84 = of 7200 В± 550 mg/kg

 

Table 1.2.1.2. Toxicity of the preparation of "arbidol" with v/zh introduction to the mouse- females

 

Dose, mg/kg                Effect, palo/vsego

2500                            0/5

3160                            0/5

4000                            0/5

5000                            0/5

3980                            1/5

6130                            2/5

7940                            4/5

10000                          5/5

 

LD50 = of 5950 В± 225 mg/kg

 

LD16 = of 4500 В± 220 mg/kg

 

LD84 = of 7850 В± 500 mg/kg

 

Table 1.2.1.3 toxicity of the preparation of "arbidol" with v/zh introduction to the male rats

 

Dose, mg/kg                Effect, palo/vsego

2500                            0/5

3160                            1/5

4000                            1/5

5000                            2/5

6130                            3/5

7940                            4/5

10000                          5/5

 

LD50 = of 5200 В± 350 mg/kg

 

LD16 = of 3800 В± 250 mg/kg

 

LD84 = of 7100 В± 400 mg/kg

 

Table 1.2.1.4 toxicity of the preparation of "arbidol" with v/zh

 

Dose, mg/kg                Effect, palo/vsego

2500                            0/5

3160                            1/5

4000                            2/5

5000                            2/5

6130                            3/5

7940                            4/5

10000                          5/5

 

LD50 = of 5000 В± 300 mg/kg

 

LD16 = of 3500 В± 200 mg/kg

 

LD84 = of 7000 В± 350 mg/kg

 

 

 

1.2.2. Clinical picture of the intoxication

 

The loss of animals with v/zh the introduction of the lethal doses of the preparation (more than 3000 mg/kg) was observed during 2-3 it was hour from moment of introduction with the phenomena of hypersalivation, shortness of breath, hyperkineses, retardation, apathy, stupefaction, short-term spasms in the agonal stage and paralysis. Fur was tousled, acrocyanosis was observed.

 

The dissection of those be killeden with v/zh the introduction of mice and rats revealed, besides the venous plethora of internal organs, subpleural and subdural hemorrhages, and also small hemorrhages in the medulla oblongata and the hemispheres of crust.

 

In remaining experimental animals on the doses less than 2000 mg/kg in the first twenty-four hours were noted the retardation, apathy, reduction in the consumption of fodder and water, diarrhea. During the remaining days the general state and the behavior of experimental animals were not differed from control group. On the dissection - without the special features. Sexual differences in the period of intoxication it was not noted.

 

That presented is above demonstrated by tables 1.2.2.1-1.2.2.5.

 

Table 1.2.2.1. Dynamics of the mass of the body of the males of the rats of (g) after v/zh of the injection of the preparation Of "arbidol" at the doses of less than 3000 mg/kg (M В± m)

 

 

Table 1.2.2.2. Dynamics of the mass of the body of the females of the rats of (g) after v/zh of the injection of the preparation Of "arbidol" at the doses of less than 3000 mg/kg (M В± m)

 

 

Table 1.2.2.3 dynamics of the consumption of water (ml/den') by rats after v/zh of the injection of the preparation Of "arbidol" at the doses of less than 3000 mg/kg (M В± m)

 

 

* - reliable differences from the background and the control (R<0.0shch)

 

Table 1.2.2.4. Dynamics of the consumption of fodder (g/den') by rats after v/zh of the injection of the preparation Of "arbidol" at the doses  3000 mg/kg (M В± m)

 

 

* - reliable differences from the background and the control (R<0.0shch)

 

Table 1.2.2.5. Mass coefficients (MK) of organs in the survived white rats with v/zh the injection of the preparation Of "arbidol"

(g/y00 g of the weight of body)

 

 

1.2.3. Data of dissection (nekropsii)

 

Mice

 

It is not established according to the data of dissection and macroscopic study of the internal organs of the survived and subjected to euthanasia animal differences between the groups and the control.

 

Mice of correct build, satisfactory nourishment. Fur was neat form, the centers of baldness it was not determined. Isolations from the natural openings was absent.

 

The visible mucous membranes were bright, smooth, pale color.

 

Breast and abdominal cavities did not contain exudation. The position of internal organs did not present disturbances.

 

Submaxillary lymph nodes and salivary glands had rounded and oval form, whitish color, moderately dense consistency, pinkish color.

 

The thyroid gland was usual value and form, reddish color. The thymus had triangular form, whitish color and only the plotnovatuyu consistency.

 

The intima of aorta was smooth, which shines. Value and form of heart did not present changes. Muscle of heart was moderately dense, brownish painting.

 

The opening of trachea and large bronchi was evenly wide. Lungs easily fell with the dissection of chest. Their surface was uniform pink painting. The tissue of lungs was by feel air.

 

Mucosa of the gullet was bright, smooth. Stomach had usual sizes, its opening was filled with food contents. Mucous membrane was plicated, uniform it was pink that color. Irritations, hyperemia were not noted. The mucous membrane of the small intestine was pink, which shines, smooth. The mucous membrane of thick was also smooth, slightly greyish color.

 

Form and value of the liver did not present changes. The cloth of the liver was moderately full-blooded. The pancreas was pink color, lobule.

 

Sizes and form of spleen did not present changes. The tissue of spleen was moderately dense consistency, dark-cherry color. The capsule of kidneys easily was removed, surface was smooth, uniform brownish- greyish color. In the section of organ crust and cerebral substance is well distinguished.

 

The adrenal glands were rounded form, whitish color and moderately dense consistency.

 

The mucous membrane of the bladder was the smooth, bright, pale painting. Body and horns of the uterus had a usual form and sizes. Ovaries had uneven surface, reddish color and moderate density. The eggs of males lay at the abdominal cavity, their surface was smooth, color - whitish, form - rounded.

 

The shells of brain were bright, thin, smooth. In the frontal sections of the expansion of ventricles it was not observed.

 

Rats

 

It is not established according to the data of dissection and macroscopic study of the studied organs of the differences between the groups of animals.

 

Fur was bright, neat form. The centers of baldness it was not observed. Isolations from the natural openings was absent. Front and rear extremities did not present changes. Of the deformations of extremities it was not observed. Teeth were preserved. The visible mucous membranes were pale, which shine, smooth. The mammary glands of females without the packings by feel. The sex organs of males are correctly expressed.

 

It was not noted with the inspection of the breast and abdominal cavities of disturbances in the position of internal organs. The leaves of pleura, pericardium and peritoneum were thin, which shine, smooth.

 

Submaxillary lymph nodes and salivary glands had rounded or oval form, smooth surface, slightly yellowish or pinkish color.

 

The thyroid gland tightly adjoined to the larynx. Its consistency was moderately dense. Value and form of deviations from the standard did not represent. The surface of section was uniform pinkish painting.

 

The thymus had triangular form, whitish color and moderately dense consistency.

 

The diameter of aorta was uniform for entire elongation. The intima of aorta was the smooth, bright, whitish painting.

 

Value and form of heart did not present changes. Muscle of heart was moderately dense, evenly brownish painting. The valves of heart were thin, smooth, which shine. In the cavity of the hearies a small quantity of liquid blood was contained.

 

Lungs fell with the dissection of chest. Value and form of their changes did not represent. The surface of lungs had uniform pink painting. The tissue of lungs was downy by feel. The opening of trachea and large bronchi was wide. Mucous membrane - shining, pink, smooth.

 

Mucosa of the gullet was bright, smooth, pale color. Value and form of stomach did not present changes. Its opening was filled with food contents. Of hyperemia, erosions, hemorrhages, which testify about the irritating action of the introduced preparation, it was not observed.

 

The opening of the 12-perstnoy gut of changes did not represent, mucosa of gut was bright, smooth, pink. The mucous membrane of the small intestine was so pink, that shines, smooth. The mucous membrane of thick gut had slightly greyish nuance, it was smooth, which shines.

 

Form and value of the liver did not present changes. The surface of the liver was smooth, uniform dark red painting. The cloth of the liver in the section was dark red. The capsule of the liver was thin, transparent. The consistency of the liver had usual density.

 

The form of the pancreas did not present changes. Gland had lobule structure, pink painting and moderately dense consistency.

 

Sizes and form of spleen did not present changes. The surface of spleen had uniform dark-cherry painting, it was smooth. The consistency of spleen was moderately dense. In the section of organ greyish small-celled follicles were separated.

 

Value and form of kidneys so did not present changes. The capsule of kidneys easily was removed. Surface was smooth, uniform brownish- greyish color. In the section of organ crust and cerebral substance is well distinguished. The consistency of kidneys was moderately dense.

 

The adrenal glands had rounded form, whitish- yellow painting and moderately dense consistency. In the section dark brown cerebral substance distinctly was separated.

 

The bladder was filled with transparent, bright urine. The mucous membrane of the bladder was the smooth, bright, pale painting.

 

Ovaries had uneven grainy surface, dark red color and rounded form. The body of womb was moderately dense, it had usual sizes, dark red color. The eggs of males were moderately dense, whitish color, usual sizes.

The shells of brain were thin, transparent. The substance of the brain was only plotnovatym by feel, the surface of the brain was smooth. It was not observed on the frontal dimensions of the expansion of ventricles.

 

Consequently, the results of toxicometry, data of nekropsii and observations of experimental animals in the postintoksikatsionnom period of acute poisoning make it possible to carry the substance of the preparation Of "arbidol" to THE I V class of slightly toxic medicinal substances (H Hodge et al clinical Toxicology of Commercial Products. Acute Poisoning. Ed. IV, Baltimor, 1975, 427 p; K.K. Sidorov, y9"e)(tablitsa 1.2.3.1). The state of survived acute intoxication animals testifies o grow prettier transference and the harmlessness of preparation at the doses, which exceed therapeutic into dozens of times.

 

 

 

Table 1.2.3.1. Degrees of the toxicity

(on Hodge and Sterner)

 

 

 

* the gradations of the degrees of toxicity with the intravenous way of introduction are determined by means of the multiplication of the values of standard doses for evaluating the toxicity of preparation with the oral way of introduction for coefficient of 0,1

 

From the parameters of action on the human organism and the environment from the point of view of hygienic rate setting the substance of the preparation Of "arbidol" relates to THE IV class of slightly hazardous substances (ALL-UNION STATE STAN. 12.1.007-76 "harmful substances. Classification and the general requirements of safety").

 

 

2. Study of the embryotoxic action of the substance of the preparation Of "arbidol"

 

2.1. Materials and the methods

 

A study of the embryotoxic action of the substance of the preparation Of "arbidol" was carry ouied into 2 stages. During the first stage was produced the estimation of the action of the preparation Of "arbidol" in the prenatal period, in the second stage - were studied the post-natal manifestations of its action.

 

Studies were carried out on the nonlinear white rats - females by weight 180-200 g, which are located on the standard ration.

 

Pairing the virginnykh females was accomplished with the intact males. The day of the detection of spermatozoids in the sheathed smears was considered as the first day of pregnancy.

 

Daily observation of the state of the animals was produced for the elongation of entire experiment: inspection, weighing, the registration of the average consumption of water and food.

 

During the first stage of a study of the preparation Of "arbidol" its introduction was achieved intragastrically (substance was dissolved in the distilled water they introduced through the atraumatic probe). The first group of females obtained preparation at the dose of 50 mg/kg, the second - 500 mg/kg. The doses of preparation corresponded by 10-fold and 100-fold therapeutic for the man, and the second is approximately 0.1 LD 50. The injection of preparation was achieved from 1 through 19 day of pregnancy. Into the same periods the orally distilled water was introduced by animal of control group. In each experimental group it was on 20 animals.

 

The dissection of females was achieved on 20 days of pregnancy, in this case was determined a quantity of corpora lutea in the ovaries, they calculated the number of packages for implantation, resorption and living fruits.

 

Each fruit underwent visual inspection and weighing. One third of fruits of each dung were fixed in the mixture Of buena for the subsequent study of internal orga'nov, remaining animals from each dung were fixed in 96% alcohol for the study subsequently of the state of bone skeleton. Internal organs were investigated according to Wilson's method in the modification OE NIIEM IT WAS FRAME. Bone tissue was studied according to Dawson's method in the modification OE NIIEM OF AMN OF THE USSR.

 

Statistical processing of experimental data was conducted with use t- criterion Of st"yudenta and criterion U of Wilcockson-Mann- Whitney.

 

In the second stage of an experimental study of the preparation Of "arbidol" its oral introduction was achieved from 1 through 21 days of pregnancy at the same doses 50 and 500 mg/kg. The distilled water was introduced by control animal. In each group posterity was obtained from 15 females. It is afterward ancestral in each dung they left not more than 8 young rats for further study of the physical development of posterity, speed of ripening sensory- engine reflexes in the period of feeding, investigating the emotional- engine behavior of young rats after the end of the period of feeding.

 

During the study of the physical development of posterity recorded the size of dung, the number of living and dead newborns, the number of individuals of different floor, the mass of the body of young rats with the 4th, the 7th, the 14th and 21-1 days after generation, and also the periods of the ungluing of the pinna, the appearance of primary hair cover, the cutting of cutters, the discovery eyes, lowering of testes and discovery of sheath.

 

The study of the speed of ripening sensory- engine reflexes in the period of feeding was conducted with the use of the following tests: revolution to the plane (2-4 days), the negative geo-taxis (5-6 days), the avoidance of break (4-6 days). Experiences were conducted 1 time in the day at the same time to the complete formation of reflexes on the tests indicated.

 

With a study of physical development and speed of ripening sensory- engine reflexes in the period of feeding the statistical processing was conducted with the use of criteria t of st"yudenta and U of Wilcockson-Mann- Whitney. The dung assumed for the unit of observation with the statistical processing.

 

At the age of 30 days in posterity was studied emotional- engine behavior with the use of a test the "open field". 10 dungs from each group underwent testing. Research was conducted with the standard diffuse illumination at the same time of twenty-four hours. Animal they placed to the center of the "open field" and during 3 minutes recorded the number of crossed squares (engine- research activity), the number of counters (tentative activity), the number of glancings into the openings (research activity), the number of reports of defecation and urinatsii (emotionalism), the time of the absence of activity. The passage of square was considered, if young rat intersected boundary with all of 4-m4 by paws, the number of defecation was evaluated according to the number of defecating balls.

Statistical processing on the test the "open field" was conducted through Wilcockson-Mann- Whitney criterion, in this case for the unit of observation one young rat assumed.

 

 

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2.2. Results of a study and their consideration

 

First stage of the study

 

The results of a study during the first stage attest to the fact that the loss or others it is indicative toxicosis in female rats it was noted neither in the experimental nor in the control room groups. Reliable differences in the rates of increase in the mass of the body of the pregnant females of experimental and control room of groups also it was not noted.

 

The results of studying the possible embryotoxic action Of "arbidola" are represented in Table 2.2.1.

 

Table 2.2.1. Study of the embryotoxic action of the preparation Of "arbidol" on the white low breed rats with the introduction at doses 50 and 500 mg/kg from the 1st through the 19th the days of the pregnancy

 

 

 

CONCLUSION

 

Intragastric introduction to the females of the rats of the substance of the preparation Of "arbidol" at doses 50 and 500 mg/kg from 1 through 19 day of pregnancy does not render the embryotoxic action: the indices of embryonic growth in both experiment groups do not have statistically significant deviations from the indices in the inspection team; physical development, rate of the development of sensory- engine functions and emotional- engine activity of posterity of the experimental and obtained preparation rats also do not show the presence of deviations.

 

Intragastric introduction to the substance of the preparation Of "arbidol" at the dose of 500 mg/kg does not render action on the reproductive function of males and females of rats. In the experiments not it was revealed negative influence on fruitfulness of experimental animals, on pre- and post-natal development of posterity.

Thus, the substance of the preparation Of "arbidol" OF THE PRIVATELY HELD COMPANY Of "masterklon" with the intragastric introduction does not render embryotoxic action and it does not influence the reproductive function of experimental animals.

 

 

 

LITERATURE

Drug registration requirements in japan (to shch-.tyu edition). Japan, Tokyo, Yakuji Nippo LTD, 1993, 306 p.

The rules governing medical products in the European Community. Volume III. Guidelines on the quality, safety and efficiency of medical products for human use. Luxembourg, Office for Official publications of the European Community, 1989, 272 p.

Babayan E.A., Lepakhin V.K. and other instructional systematic materials on the experimental and clinical study of new medicines. Publication is official, part of 6. M., 1986, 272s.

Bayley N. statisticheskiye are methods in biology. M., "worlds", 1963, 271 s.

Buresh 4., Bureshova O., Houston J. p. materialy and basic experiments on the study of the brain and behavior. M., "higher school", 1991, 397 s.

Gatsura EXPLOSIVE the methods of a primary pharmacological study of biologically active materials. M., "medicine", 1974, 143 s.

Kigel' g. b., Kharabadzhakhyan YA.V. the indices of biological standard for laboratory animals. To Rostov-on- Don, 1978, 95 s.

Rules of the preclinical safety evaluation of pharmacological means (RD 64-126-91). M., MZ of Russia, FK, 1992, 45 s.

Problems of standard in the toxicology (edited by Prof. OF I.M. Trachtenberg). M., "medicine", 1991, 203 s.

Prozorovskiy V.B., Prozorovskaya M., Demchenko V.M. the rapid method of the determination of average effective dose and its error - Farmakol. and toksikol., 1978, в„– 4, s. 497-502.

Instructional systematic materials on the experimental and clinical study of new medicines (official publication). Parts 1, 3. Pharmacological committee. M., 1975, 1981.

Reference book on functional diagnostics. Edited by The the i.A.Kassirskogo. M., Is copper. 1970, 849 s.

Requirements for the preclinical study of the systemic toxic effect of new pharmacological substances (temporary systematic recommendations). M., MZ USSR - Ministry of Public Health of the USSR, FK, 1985, 19 s.